Clinical Significance of Immune Imbalance and Autoimmunity in Nervous System Disorders (NSDs)

Clinical Significance of Immune Imbalance and Autoimmunity in Nervous System Disorders (NSDs)
Singh, Vijendra K.
2015-09-01 00:00:00
In recent years, the role of immune imbalance and autoimmunity has been experimentally demonstrated in nervous system disorders (NSDs) that include Alzheimer's disease, autism, obsessive-compulsive disorder (OCD), tics and Tourette's syndrome, schizophrenia, and some other NSDs. And yet, these NSDs are never counted as autoimmune diseases. Deriving from the rapidly expanding knowledge of neuro-immunology and autoimmune diseases, for example multiple sclerosis (MS), the author of this mini-review strongly recommends that these NSDs should be included while tallying the number of autoimmune diseases. This effort will help create an updated global database of all autoimmune diseases as well as it should help treat millions of patients who are suffering from debilitating NSDs for which there is no known cure or treatment currently. Keywords: CNS disorders; autoimmune diseases; neuro-immune diseases Coresponding address: Vijendra K. SINGH Neuro-Immune Biotechnology Solutions (NIBS) Bellingham, WA 98229 USA E-mail: vj.nibs@gmail.com , . , . (), 50 . () (1­6). (), , , - (), , Tourette (). , (). . , , ( ), . , . , . 40 , (65-85%) (2). . 3 4 , 7080% (5, 6). . , Tourette () - () . Introduction 1. Nervous System Disorders as Autoimmune Diseases Globally speaking, autoimmunity is one of the most common problems in chronic diseases in man. Relying on scientific criteria, approximately eighty-five or so medical conditions are commonly regarded as autoimmune diseases. According to American Autoimmune Diseases Related Association (AADRA), more than 50 million Americans and millions more worldwide are known to suffer from autoimmune diseases. This number however never includes many more individuals who suffer from nervous system disorders (NSDs) and who have evidence of autoimmunity as demonstrated by laboratory testing (1-6). The examples are Alzheimer's disease (AD), autism, schizophrenia, obsessive-compulsive disorder (OCD), tics and Tourette's syndrome (TS). There is one exception to this category of NSDs which is multiple sclerosis (MS). MS is always accounted for in the epidemiological database of autoimmune diseases. Thus, to start with, the author would herby like to suggest that future epidemiological studies must take into the account that there is a new patient population that suffers from neurological problems (brain diseases and mental illnesses) and yet shows typical characteristics of an autoimmune disease. Once this is done, the number of people affected with autoimmune diseases will dramatically increase throughout the world. To that end, let us examine the number of people affected with NSD. Alzheimer's disease affects an estimated 40 million Americans and a large proportion (65-85%) of the sporadic form of AD has autoimmune problems (2). This will represent a huge number to be considered in the category of autoimmune diseases. Autism and related spectrum disorders affects 3 to 4 million children and adults in the United States and 70-85% of them have well-characterized autoimmune problems (5, 6). This will also represent a large number to be included in the category of autoimmune diseases. Likewise, many more people with tics and Tourette's syndrome (TS) and obsessive-compulsive disorder (OCD) have been shown to have autoimmunity to brain. This population should . . , . also be included in the same category of autoimmune diseases. Quite clearly then the number of autoimmune diseases will rise sharply if this new category of nervous system diseases involving autoimmunity are included in the epidemiological studies. This has not been done so far but their numbers should be tallied in future epidemiological studies. 1. , , . , . , , . 30 , . 1. , , - (), - () Figure 1. Reciprocal Relationship between Immune System and Nervous System If you have an autoimmune disease, your immune system goes haywire and begins to attack healthy cells, tissues and organs. However this must happen in a highly select way. Thus, in the case of brain autoimmunity, the immune system will elicit autoimmune response against the brain or nerve tissue. Approximately 30 years ago, we recognized the importance of a reciprocal relationship that existed between our immune system and nervous system. This is illustrated in Figure 1. As illustrated here, the immune and nervous systems are interconnected with each other and this relationship is mediated by chemical messengers, for example cytokines produced by immune system cells like T helper cells (TH), T suppressor cells (TS) and antigenpresenting cells (APC) whereas neurotransmitters and neuropeptides produced by . , . , 30 , , , (7). , , , , , . , . . , . , , , (8). 2. , , . 1, - () -6 (-6) , , () . (9). (6) , . , 104 neurons and glial cells. As we know it now, this relationship occurs at both the cellular level as well as the molecular level. But nearly 30 years ago, we postulated that the disruption of this neuro-immune or immune-neural circuitry might actually be the reason underlying a wide-range of brain diseases and mental illnesses (7). Environmental factors such as a viral or bacterial infection, trauma or brain injury, and other dietary factors can easily break down this circuitry. In that regard, one of the most important findings in the field is the observation that autoimmune disease of the nervous system is the most common problem when the neuro-immune circuitry breaks down. This should prove to be clinically quite relevant because autoimmune diseases of the nervous system could be medically recognized and be treated with immune therapies that are currently being used for other autoimmune diseases. This is already beginning to happen as exemplified by immune therapy for individuals with autism, OCD and TS. Recently, we hypothesized that the disruption of neuro-immune circuitry could cause neuro-immune imbalance in the body, thereby it may also affect brain plasticity, brainwave pattern, and brain function (8). 2. Link between Infections and Nervous System Disorders What causes autoimmune diseases is still unknown but it is commonly recognized that they are triggered by environmental factors, in particular viruses. As summarized in Table 1, the examples include Epstein-Barr virus (EBV) and human herpes virus-6 (HHV-6) in MS, measles virus in autism, herpes simplex virus (HSV) in AD, and streptococcal infection in OCD and TS. More recent studies have found a much closer involvement of EBV in MS (9). As recently described in a much greater detail elsewhere (6) and when properly evaluated by specialized immune tests, just about every second autistic child has elevated level of antibodies to measles virus. This is not an exaggeration but a real scientific fact deriving from solid laboratory research , () . , . , (2­4). 1. () () / Nervous System Disorder (NSD) - / Immunoregulatory T-cells 4 / CD4+ Helper cells / Down 8 / CD8+ Suppressor cells / Up involving children with typical form of autism but not the children with autistic spectrum disorders (ASD) which includes a highly heterogeneous diagnosis of neurobehavioral disorders. Virus infections are now known to change the permeability of the blood-brain barrier, which permits the entry of immune cells and proteins into the brain. Inside the brain, the microglial cells can also produce pro-inflammatory cytokines that are involved in the autoimmune process known as neuroinflammation or inflammation of the brain (2­4). Table 1. Immune Imbalance in Patients with Nervous System Disorders (NSDs) / Immunosurveillance / NK cells / Down / Autoimmunity / Brain Autoantibodies* (, ) / Yes (MBP, CN, Serotonin receptors) () / Yes (CN) (40 / Yes (AP40, cholinergic cells) () / Yes (MBP) () / Yes (Not known) () / Yes (Not known) () / Yes (MBP) () / Yes (CN) / Infection / Virus or Bacteria () / Yes (Virus) / Autism - () / Obsessive-Compulsive Disorder (OCD) () / Alzheimer's Disease (AD) () / Multiple Sclerosis (MS) () / Major Depressive Disorder (MDD) / Alcoholism / Schizophrenia Tourette () / Tourette's Syndrome (TS) / Down / Down / Down / Down / Down / Down / Down / Up / Down / Down / Down / Down / Down / Down / Down () / Yes (Bacteria) () / Yes (Virus) () / Yes (Virus) (/) / Yes (Virus/Bacteria) / Not known () / Yes (Virus) () / Yes (Bacteria) / Up / Up / Up / Up / Up / Up / / Up / / Not () / Yes Down Down known (Virus) () / Chronic Fatigue Syndrome (CFS) *MBP=Myelin Basic Protein / ; CN=Caudate Nucleus / ; AP40=Amyloid-beta-protein (1-40) / ; Serotonin receptors=Brain receptor proteins that binds to serotonin neurotransmitter / = ; Cholinergic cells=Acetylcholine neurotransmitter containing cells/ = . . #1-7, 10 and 13. 3. 30 (7). - : , , , . . , ( 1). ( , ), , . , , , . , nucleus caudatus , , . nucleus caudatus ( ) (10), nucleus caudatus (11-12). -12, , (13). , 3. Neuro-Immune Imbalance in Nervous System Disorders Some 30 years ago, we also recognized that our immune system vastly impacts our nervous system (7). This prompted Dr. Singh to study the role of immune system in NSDs for two main reasons: First, this might help discover biomarkers for brain diseases and mental illnesses, and secondly, it might also help find novel approach to therapy with immune modulating agents for these neuro-disorders. The fruits of labor are now beginning to payoff because many researchers are now finding positive results. Similar to all other typical autoimmune diseases, the experimental evidence for autoimmunity to brain or neuroautoimmunity has been found in NSDs (see Table 1). The positive test results include specialized proteins of the immune system (for example, antibodies and cytokines), autoimmunity testing, and immunotherapy. Immune activation, which is the first step in the onset of autoimmunity, has been shown in patients with autism, MS, AD, TS and OCD. Patients with these diseases also harbor elevated levels of autoantibodies that bind specifically to brain proteins, for example antibodies to caudate nucleus of the basal ganglia in autism, TS, and OCD, antibodies to amyloid protein-beta in AD, and antibodies to myelin basic protein in autism and MS. It's interesting to point out that subsequent to the original finding of antibodies to caudate nucleus (located deep within the brain) in autistic children (10), some researchers have now found neuroimaging evidence of structural and functional abnormalities in the caudate nucleus of children with autism (11-12). Interferon-gamma and interleukin-12, the two proteins of the immune system that initiate autoimmunity, are also activated in patients with brain diseases (13). Furthermore, many patients also show improvement when administered with immunotherapy using intravenous immunoglobulin, plasmapheresis, transfer factor, and other , -, - (3, 5, 6). Tourette (), . - 1- (14). . , 2 . 2 nucleus caudatus (15) ­ , ( . #10). , 2, - (16). 4. . () ­ . , , , , . , . , , immune modulating agents (3, 5, 6). With regards to Tourette's syndrome (TS), a recent study has linked histamine neurotransmitter system in TS and tics. Researchers have identified a rare mutation in the HDC complex that encodes 1-histidine decarboxylase enzyme involved in histaminergic neural pathways (14). The study suggests that the patients with TS might not be making enough histamine and this reduction in histamine might impair the function of histamine receptors in brain. Histamine has different receptors in the brain, for example H2 type receptors. It is of considerable interest that H2 receptors are enriched predominantly in corpus striatum or caudate nucleus (15) ­ a brain structure which is also targeted by autoimmunity in patients with autism, TS, OCD (see cross-ref. #10). Thus it is tempting to speculate that these patients might actually have autoantibodies to brain histamine H2 receptors, much like autoantibodies to brain serotonin receptors in children with autism (16). 4. Novel Findings for Autoimmune Diseases There are some interesting new findings for autoimmune diseases that may also be relevant to autoimmunity in nervous system disorders. Autoimmune diseases are associated with oxidative stress (OS) ­ a sign of reduced function of energy-producing intracellular organelles called mitochondria. Using white blood cells, mainly lymphocytes, the OS has been found in patients with neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, schizophrenia and autism. In this regard, a very recent study has shown that OS involves a biochemical defect of a key mitochondrial enzyme called NADP oxidase. Since the OS was found using lymphocytes, this finding may be interpreted as reduced energy level for immune cells, which could ultimately - . - (-), -, () . - , . , . - , . . - . , ­ (17). , -. , . , . , 108 lead to imbalance of immunoregulatory T cells causing autoimmunity and inflammation. Interferon-gamma (IFN-gamma), a proinflammatory cytokine produced mainly by T cells, has been shown to increase the expression of immune protein called major histocompatibility complex (MHC) in the brain. IFN-gamma is well known to increase the expression of MHC on neural cells and thereby increase the permeability across the blood-brain barrier. Recently it was found that the enhanced expression of MHC is related to abnormal brain development, which would suggest a role for this protein in disorders like autism and schizophrenia. Since IFNgamma is a key cytokine inducer of autoimmune response and it is elevated in patients with autism and Alzheimer's disease, the expression of MHC might also be related to autoimmune pathology of nervous system disorders. Vitamin D has recently been found to play a crucial role in activating immune response defenses. It controls human Tcell function to elicit an effective immune response against invading viruses and bacteria. It was found that without sufficient intake of the vitamin, the killer cells of the immune system -- T cells -will not be able to react to and fight off serious infections in the body (17). Thus the insufficient amount of vitamin D can cause imbalance of immunoregulatory T cells. Since these cells are abnormal in autoimmune diseases, vitamin D will play a vital role in nervous system disorders. Indeed, many patients with nervous system disorders are deficient in vitamin D and therefore a daily intake of this vitamin is highly recommended. In that regard, vitamin D deficiency has recently been found in children with autism and the oral intake of this vitamin was shown to improve core characteristics in autistic children (18). It is quite possible that (18). -; -, . . . . , (19). , (). , , . - . - ­ . - - (20). - , . , , . , . vitamin D supplementation might improve the function of T cells; the T-cell number as well as the function is wellknown to be decreased in children with autism. Poor leep or sleep deprivation increases inflammation as shown by elevated level of CRP. This serum protein is an acutephase protein and is associated with autoimmune disease. This finding is relevant to nervous system disorders. For example, children with autism generally are sleep deprived and do not have good sleep patterns and elevated levels of CRP have been found in children with autism (19). There is reason to believe that stem cell therapy can be used to help patients with autoimmune diseases, including nervous system disorders (NSDs). Stem cells, in particular those of the bone marrow, are committed to become immune cells like lymphocytes. IFN-gamma is a front-line immune defender against microbial infections. It also regulates normal development of immune cells from bone marrow-derived stem cells ­ the process is known as hematopoiesis. A recent study has now found that IFN-gamma prompts and promotes the production of immune cells from bone marrow progenitor stem cells during bacterial infections (20). Because IFN-gamma is a proinflammatory cytokine, this finding has tremendous potential for immune therapy with stem cells for nervous system disorders. This would be a novel mechanism for stem cells to produce normallyfunctioning immune cells that in theory should help overcome immune imbalance and therefore autoimmunity. Alternative approach would be to use growth factors and other nutraceuticals to provide an environment that will be conducive to yielding immune cells, neural cells or other type of cells. Among various factors, vitamin C is being used to culti109 , . , . , , . , . vate and harvest neural cells in tissue culture systems of the stem cells. When people think of stem cell therapy for neurological diseases they only think of repairing nerve cells in the brain. But there should be more emphasis in reconstituting immune cells since the immune cells vastly impact nervous system function. Ideally speaking, the attempt should be to rebuild both the nerve cells as well as the immune cells from stem cells. , o (). , . . ( , ) , . () . , ,, ", ­ 6 , 2009 (21). , - ( - -). , Concluding remarks In summary, several lines of scientific evidence suggest a pathogenic role of immune imbalance and brain autoimmunity in nervous system disorders (NSDs). Concerning the future directions of NSDs, the first step is to account for the NSDs patient population in all future epidemiological studies if we are going to realize the actual impact and financial burden of autoimmune diseases in our society. Immunotherapy with immune modulating agents offers a novel promising approach to helping people affected with these medical conditions. Autoimmunity in the brain (for example, binding of antibodies to brain antigens) may also cause a shift in brain waves thereby resulting into a functionally "imbalanced brain." This type of autoimmune injury to brain would in fact be very similar to traumatic brain injury (TBI) and the outcome may be a life-long event. Thus, the author of this article strongly suggests that the immune therapy should be administered first to bring about "Immune Balance" before administering medical or alternative treatment for nervous system disorders ­ an idea he originally proposed about 6 years ago in 2009 (21). It is furthermore implied that the immune balance means establishing a normal balance of immuneregulatory function of T cells (balance between T helper and T suppressor cells). It should also be noted that this approach is totally different from the approach of simply boosting or suppressing the immune function which is . . , , . () . 85% , . . , . , , . . currently done by professionals all over the world. This approach might be particularly suitable and effective in patients who receive neuro-therapies and neurofeedback technology to balance the brain function. Naturally, therefore, the immune balance would be a prerequisite for treating NSDs. According to the World Health Organization (WHO), the financial burden of all brain diseases and mental illnesses surpasses that of cancer and heart disease. Since up to 85% of patients with nervous system disorders have scientific evidence of autoimmunity, a huge number of this patient population could potentially be helped by immune balancing modalities to target autoimmunity in the brain. The first step is to recognize that a vast majority of NSDs involving autoimmunity are autoimmune diseases similar to all other medically-recognized autoimmune diseases. Then, the immune balance first before the neurotherapy might very well prove to be a novel approach to helping patients suffering from NSDs. Who knows someday in not too distant future the healing power of neuro-immune balancing act might very well turn out to be one of the most important endeavors for helping people with nervous system disorders (NSDs). This naturally calls for extensive experimental research and unbiased careful attention of researchers and medical professionals throughout the world. . /
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Clinical Significance of Immune Imbalance and Autoimmunity in Nervous System Disorders (NSDs)